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The underlying mechanism of prodromal PD: insights from the parasympathetic nervous system and the olfactory… Liu, Shu-Ying; Chan, Piu; Stoessl, A. J Feb 20, 2017

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REVIEW Open AccessThe underlying mechanism of prodromalPD: insights from the parasympatheticnervous system and the olfactory systemShu-Ying Liu1,2,3, Piu Chan1,2 and A. Jon Stoessl3*AbstractNeurodegeneration of Parkinson’s disease (PD) starts in an insidious manner, 30–50% of dopaminergic neuronshave been lost in the substantia nigra before clinical diagnosis. Prodromal stage of the disease, during which thedisease pathology has started but is insufficient to result in clinical manifestations, offers a valuable window fordisease-modifying therapies. The most focused underlying mechanisms linking the pathological pattern and clinicalcharacteristics of prodromal PD are the prion hypothesis of alpha-synuclein and the selective vulnerability of neurons.In this review, we consider the two potential portals, the vagus nerve and the olfactory bulb, through which abnormalalpha-synuclein can access the brain. We review the clinical, pathological and neuroimaging evidence of theparasympathetic nervous system and the olfactory system in the neurodegenerative process and using thetwo systems as models to discuss the internal homogeneity and heterogeneity of the prodromal stage of PD,including both the clustering and subtyping of symptoms and signs. Finally, we offer some suggestions on futuredirections for imaging studies in prodromal Parkinson’s disease.Keywords: Parkinson’s disease, Prodromal, Alpha-synuclein, Parasympathetic nervous system, Olfactory system,SubtypeBackgroundParkinson disease (PD), characterized by its motorsymptoms (bradykinesia, resting tremor, and rigidity) [1],does not start suddenly. By the time the clinical diagnosishas been made, some 30–50% of dopaminergic neuronshave been lost in the substantia nigra [2]. Symptomatictreatments are effective in most patients with PD, but cur-rently no drugs have demonstrated convincing evidence ofdisease modification. One possible explanation is that thepathology of PD may be sufficiently advanced at the pointof diagnosis that none of the interventions can rescue theremaining dying neurons, thus the prodromal stage of PD,during which the disease pathology has started but is in-sufficient to result in clinical manifestations, provides avaluable window during which disease-modifying therap-ies can be tested [3].According to recent Movement Disorder Societycriteria, early PD can be divided into three stages:preclinical PD (neurodegeneration has started yetwithout evident symptoms and signs); prodromal PD(symptoms and signs are present, but are still insuffi-cient to define PD) and clinical PD (diagnosis of PDbased on classical symptoms). The criteria are basedupon probability and likelihood since it is not pos-sible to identify prodromal PD with 100% certainty;probable prodromal PD is defined as a high likelihood(greater than 80%) and possible prodromal PD as alikelihood between 30 and 80% [4, 5]. The cardinalfeatures of prodromal PD are non-motor and includeconstipation, hyposmia/anosmia, depression, REMsleep behavior disorder, orthostatic hypotension, andloss of heart rate variability [6]. Notably, many of thesymptoms that emerge earlier in the disease coursecan be attributed to dysfunction in the peripheral ner-vous system or the peripheral part of the central ner-vous system, such as the vagus nerve (e.g. constipation),* Correspondence: jstoessl@mail.ubc.ca3Pacific Parkinson’s Research Centre, Division of Neurology and DjavadMowafaghian Centre for Brain Health, University of British Columbia andVancouver Coastal Health, Vancouver V6T 1Z3, BC, CanadaFull list of author information is available at the end of the article© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Liu et al. Translational Neurodegeneration  (2017) 6:4 DOI 10.1186/s40035-017-0074-8the sympathetic nervous system (e.g. orthostatichypotension), or the olfactory bulb (hyposmia).Neuronal aggregation of alpha-synuclein (α-syn) inLewy bodies and Lewy neurites, the pathological signatureof sporadic PD, can be found in the peripheral nervoussystem of PD patients [7]. It is not clear whether thesestructures are the original site of α-syn aggregation orwhether they are subject to α-syn pathology transportedfrom the brain. In support of the former hypothesis, trun-cal vagotomy has been associated with a reduced risk ofPD after 20 years of follow-up (adjusted hazard ratio [HR]= 0.53; 95% CI: 0.28–0.99) [8]. Based on evidence fromhuman studies, cell culture and animal models, the para-digm of pathological protein propagation in neurodegen-erative diseases has been extended to include the conceptthat pathology arising from neurodegeneration-relatedproteins such as α-syn, amyloid-β, tau and TAR DNA-binding protein 43 (TDP43) may propagate in a prion-likefashion [9–13]. On the other hand, the prion hypothesisas selective neuronal vulnerability may be another import-ant factor contributing to specific patterns of degenerationin human and animal brains [13]. In PD patients whounderwent human fetal nigral transplantation, Lewy body-like inclusions that stained positive for α-syn were foundin the grafted nigral neurons 14 years after transplant-ation, suggestive of cell to cell transmission [14, 15]. It ishypothesized that the propagation of α-syn in the brainstarts in the dorsal motor nucleus of the glossopharyngealand vagus nerves (DMV) and the olfactory bulb; fromthese two structures the α-syn pathology spreads in an as-cending pattern to the pons, the midbrain, the basal fore-brain and finally to the neocortex through chains ofvulnerable neurons [16–18]. The so-called “Braak hypoth-esis” provides a mechanistic underpinning for the pro-dromal stage of PD, as non-motor symptoms could beexplained by pathology in the peripheral nervous systemand caudal brainstem that precede the onset of classicmotor symptoms which do not emerge until Lewy path-ology affects the substantia nigra. In this review weconsider the two potential portals through which abnor-mal α-syn can access the brain: the vagus nerve and theolfactory bulb. We review clinical, pathological and neuro-imaging evidence, and suggest future directions for studiesin prodromal disease.Constipation and the parasympathetic nervoussystemRisks of PDConstipation is a non-specific yet sensitive prodromalsymptom of PD (sensitivity 79%, specificity 31% fromHonolulu-Asia Aging Study) [19, 20]. At 10 years beforediagnosis of PD, the incidence of constipation wasalready higher in those who went on to develop PD thanin controls (relative risk [RR] = 2.01; 95% CI: 1.62–2.49)while the incidence of other typical prodromal symp-toms (except tremor) fails to reach significance until5 years before diagnosis [21]. To date, eight large longi-tudinal cohorts confirmed the increased risk of PD inpopulations with chronic constipation [19, 21–27], pro-viding sufficient evidence for the Movement DisorderSociety task force to calculate a likelihood ratio (LR) forconstipation in the research criteria for prodromal PD(constipation LR + = 2.2, LR− = 0.8) [5].Underlying mechanisms and the role of α-synThe mechanism of constipation in PD and prodromal PDis still under debate. A-syn deposition and Lewy type α-syn pathology affecting the gastrointestinal tract have beenfrequently reported from biopsy and postmortem studies;however, the types of antibodies, the morphological as-sessment of pathology and the site of biopsy varied con-siderably, in line with the inconsistent measures ofsensitivity and specify of α-syn pathology detected be-tween patients and healthy aged controls [28, 29]. Amongthe many contradictory results, one of the more consistentfindings is a rostral-caudal gradient of α-syn pathologythroughout the gastrointestinal canal (most dense in thelower esophagus, stomach, and upper small intestine; low-est in the colon and rectum) [7, 30], which correspond tothe rostral-caudal gradient of vagal innervation [31]. TheDMV is one of the earliest sites of α-syn aggregation inthe central nervous system according to Braak, and morethan 50% of efferent motor neurons were already lost bythe time that clinical PD became manifest [32]. It is hy-pothesized that the accumulation of α-syn may originatein the enteric nervous system and be transported in aretrograde manner through the vagus nerve. By inducingnormal α-syn to misfold in a prion-like manner, the cyclemay repeat itself and lead to self-propagation and cell lossin networks of connected neurons [13].In retrospective pathological studies of PD patientswho underwent colon biopsy years before being diag-nosed with PD, α-syn pathology in the gastrointestinaltract could be detected up to 20 years prior to the fullmanifestation of PD symptoms [33–35]. In one study ofpatients with REM sleep behavior disorder (RBD), whichcarries a high risk of future synucleinopathy, immuno-staining of phosphorylated α-syn was reported in four of17 subjects, whereas none of the 14 healthy controls waspositive [36]. Even though these findings support the ac-cumulation of α-syn in the gut as a possible peripheralmechanism for constipation, caution is required owingto inconsistency of findings and the absence of directevidence of centripetal spread of α-syn in humans.There is recent evidence for alterations in the gutmicrobiome in PD [37–39]. Whether gut microbial con-tent is altered as a manifestation of impaired colonicLiu et al. Translational Neurodegeneration  (2017) 6:4 Page 2 of 9motility or whether altered GI flora can result in re-gional neurotoxicity remains to be determined.Evidence from medical interventionsBased on clinical and pathological evidence, further in-vestigations were conducted into the potential neuropro-tective effects of gastrointestinal interventions such asvagotomy and appendectomy. A small cohort with 34patients who underwent appendectomy before PD onsetshowed that past appendectomy may be associated withmore years of life without PD symptoms (P = 0.040) [40],however, a later population-based study of 265,758 pa-tients with appendectomy and 1,328,790 comparisoncontrols indicated no difference in risk of PD betweensubjects with or without appendectomy in mid or latelife (HR = 1.00; 95% CI: 0.74–1.36) [41].. On the otherhand, Svensson et al. assembled a population-basedregistry-linkage cohort with 14,883 patients who under-went vagotomy between 1977 and 1995 and analyzedthe incidence rates and HR of PD afterwards, the overalladjusted HR between patients with truncal vagotomywas 0.85, 95% CI: 0.63–1.14; for those with follow-up ofmore than 20 years, adjusted HR was 0.53, 95% CI:0.28–0.99 [8]. The study is the first evidence that by pre-venting vagal transport, the risk of PD decreased, sup-porting a possibly critical involvement of the vagusnerve in the pathogenesis of PD.Evidence from imagingPositron emission tomography (PET) offers a useful toolto investigate physiological dysfunction in vivo [42]. In2014, the PET tracer 5-11C-methoxydonepezil was vali-dated for the in vivo quantification of acetylcholinester-ase (AChE) density in humans and thus can serve as abiomarker for parasympathetic dysfunction. Significantlydecreased 11C-donepezil standard uptake values in thesmall intestine and pancreas were detected in twelve PDpatients compared to age-matched controls (small intes-tine: −35%, P = 0.003; pancreas: −22%, P = 0.001); the re-sults were similar when distribution volume wasassessed (small intestine: PD 66.4 ± 15.4 control 111.9 ±40.0, P = 0.001; pancreas: PD 126.2 ± 31.7 control 167 ±64.2, P = 0.061) [43]. Interestingly, the rostral-caudal pat-tern of vagal innervation was replicated by the distribu-tion of 11C-donepezil binding: highest in the uppergastro-intestinal tract and lower in the ileum and colon.This study supports suggestions of impaired vagal activ-ity in PD patients but there was no relationship betweenreduced cholinergic activity and severity of PD. However,reduced 11C-donepezil uptake is not specific for de-creased vagal innervation, as it might also reflect the lossof cholinergic enteric neurons.Hyposmia and the olfactory systemRisk of PDThe other potential portal for aggregated α-syn to enterthe central nervous system are the anterior olfactorystructures. Olfactory loss demonstrated by objective testis the only non-motor symptom that has more than 80%specificity for the differential diagnosis of PD from otherparkinsonian conditions in the MDS clinical diagnosticcriteria [1]. Hyposmia is also predictive of the future de-velopment of clinical PD in both general and high-riskpopulations, but with lower specificity (sensitivity 79%,specificity 53% from Honolulu-Asia Aging Study; sensi-tivity 60%, specificity 72.6% from Prospective Validationof Risk factors for the development of Parkinson Syn-dromes study) [20, 44, 45]. Based on the predictive valueof olfactory dysfunction and dopaminergic deficit indopamine transporter (DAT) imaging, the nestedpopulation-based Parkinson Associated Risk Syndromestudy was launched from 2008: 4999 subjects completeda 40-item University of Pennsylvania Smell IdentificationTest (UPSIT) in the first stage; 203 hyposmic subjectsand 100 normosmic subjects underwent 123I-ß-CIT/SPECT at the baseline of the second stage [22, 46]. Theresults demonstrated a significant predictive ability ofhyposmia for dopaminergic dysfunction (odds ratio[OR] = 12.4, 95% CI: 1.6–96.1) at baseline and a 61%phenoconversion rate of subjects who had both hypos-mia and DAT deficit (of whom there were only 23) inthe 4-year follow-up [47]. For high-risk populations,Postuma et al. reported that the UPSIT scores of RBDpatients who developed PD in 10 years were much lowerat baseline than RBD patients who remained disease-free(HR = 2.8, 95% CI: 1.3–6.0, P = 0.003) [48]. Similar re-sults were found in an RBD cohort from Spain and in acohort of first degree relatives of PD [49–51]. TheMovement Disorder Society task force determined a LR+ of 4.0 and a LR− of 0.43 for olfactory dysfunction inthe research criteria for prodromal PD [5].Underlying mechanisms and the role of α-synHyposmia/anosmia in PD could reflect both cortical andlocal pathological changes and likely involves a complexintegration of central network deficits and local neuraldysfunction, in which the role of α-syn may be critical.The olfactory receptor neurons are directly exposed tothe external environment and thus prone to attack fromviruses, toxins or other pathological particles. The axonsof the olfactory neurons pass though the cribriform plateand reach the mitral or tufted cells in the olfactory bulb,whose axons project in turn to the anterior olfactory nu-cleus, the piriform cortex, the periamygdaloid cortex,the olfactory amygdala and entorhinal cortex [52, 53]. A-syn pathology in the olfactory mucosa of PD patientsdoes not appear to be greater than that in healthy age-Liu et al. Translational Neurodegeneration  (2017) 6:4 Page 3 of 9matched controls [54, 55], while in the olfactory bulbthere is evidence for abnormal α-syn deposition that dis-tinguishes PD subjects from healthy elderly controlswith a sensitivity of 95% and a specificity of 91% [56].The anterior olfactory nucleus, which receives inputfrom the mitral and tufted cells, was the most heavily in-volved structure in the bulb region; the cortical nucleusof the amygdala, which receives input from the primaryolfactory bulb projections, exhibited considerably moreα-syn pathology and neuronal loss than other amygdal-oid nuclei [53, 56]. The extent of α-syn pathology inother brain regions, including substantia nigra, amyg-dala, cingulate cortex and orbitofrontal cortex, wasstrongly correlated with pathological burden in the ol-factory bulb in the brains of patients with Lewy bodydiseases [56, 57]. In a small cohort of PD and incidentalLewy body disease cases, α-syn pathology was found inall sub-regions of the primary olfactory cortex. Despitethe fact that all the sub-regions are separated from theolfactory bulb by only a single synapse, the burden of α-syn pathology varies: highest in the frontal and temporalpiriform cortex and lowest in part of anterior entorhinalcortex [58]. Together, these results support the possibil-ity that the pathology of PD spreads along olfactorypathways but is additionally influenced by differentialneural vulnerability.Evidence from animal models showed that after injec-tion of preformed fibrils of recombinant α-syn into theolfactory bulb, wild-type mice developed not only olfac-tory deficits, but also α-syn pathology in brain areas un-connected to the olfactory system after a time interval ofabout half a year [59]. Similar changes were seen follow-ing intranasal instillation of pro-inflammatory lipopoly-saccharide [60]. Widespread propagation of α-synpathology through connected anatomical pathways wasobserved in the animal study: 1 month after intranasalinjection, α-syn phosphorylated on serine 129 (Pser129)was found in areas directly connected to the olfactorybulb, including piriform cortex, entorhinal cortex andcortical amygdaloid nuclei; 3 months after, the pathologyhad progressed to those brain areas one synapse re-moved from the olfactory bulb, including the hippocam-pus, insular cortex and frontal cortex; by 6 monthsPser129-positive cells were found two synapses removedfrom the olfactory bulb and 12 months later Pser129pathology was widespread in cortical associative and sec-ondary cortical brain regions, somatosensory cortex andthe anterior cingulate area [59]. The propagation modelwas created using preformed fibrillary assemblies of re-combinant α-syn in mice, thus may provide only an in-direct simulation of the behavior of α-syn in the humanolfactory system.In the aged human population, a postmortem studywas performed in 164 participants who underwentolfactory testing during the longitudinal Honolulu-AsiaAging Study; incidental Lewy bodies were found in thesubstantia nigra or locus coeruleus in only 1.7% of sub-jects in the highest tertile of olfactory performance, butin 18.2% of subjects in the lowest tertile, with an age-adjusted OR of 11.0 (95% CI: 1.3–526) [61]. In anotherstudy with 320 consecutive autopsies from a generalgeriatric hospital, α-syn pathology restricted to the olfac-tory bulb was detected in 16 subjects (2% of all partici-pants), of whom two had α-syn pathology in the anteriorolfactory nucleus alone, and 14 in the peripheral olfac-tory bulb [62]. In accordance with the results from pre-vious studies, the extent of α-syn pathology in theamygdala was strongly correlated with that in the olfac-tory bulb (Spearman correlation R [RS] = 0.853) [56, 62].Similar results were reported from elderly subjects withincidental Lewy body disease or Alzheimer’s disease withLewy bodies [7, 63].Evidence from imagingAnterior olfactory structuresMorphological analysis by structural magnetic reson-ance imaging (MRI) can be used to provide quantita-tive measurements of anatomical changes of brainstructures, including volume, cortical thickness or shape.A meta-analysis of six case-control studies showed signifi-cant reduction of olfactory bulb volume in PD patientscompared to heathy controls, the pooled weighted meandifference was −8.07 mm3 (95% CI: −14.72, −1.42) for theright olfactory bulb and −10.12 mm3 (95% CI: −16.48,−3.77) for the left olfactory bulb [64]. However, the resultsmust be interpreted with caution as the heterogeneity be-tween studies was quite high (I2 = 76%). Another studycompared the volume of both olfactory bulb and tractsbetween patients with PD and with other forms of parkin-sonism including progressive supranuclear palsy (PSP),multiple system atrophy (MSA), and corticobasal degener-ation (CBD) and detected the lowest volume of 198.3 ±60.1 mm3 in patients with PD, followed by 261.7 ±75.5 mm3 in PSP, 278.2 ± 77.0 mm3 in MSA, 312.4 ±30.2 mm3 in CBD, and 314.6 ± 42.6 mm3 in controls [65].Using diffusion tensor imaging (DTI), two studies re-ported a significant increase of mean diffusivity, presumedto reflect axonal and myelin damage, in bilateral olfactorytracts of the PD patients. The mean diffusivity values ofthe olfactory tract and substantia nigra were significantlycorrelated with decreased 6-[18F]-fluorolevodopa uptakein the putamen (R = −0.71, P < 0.01; R = −0.52, P < 0.05 re-spectively) [66, 67]. The findings implied that microstruc-tural degradation of the olfactory tract and the substantianigra parallels progression of putaminal dopaminergicdysfunction, but the time sequence of the pathologicalchanges cannot be determined from these studies. MRIand DTI measurements of olfactory bulb/tractLiu et al. Translational Neurodegeneration  (2017) 6:4 Page 4 of 9degradation were associated with decreased olfactory per-formance [68, 69].Network and neural transmitter systemsThe process of odor identification requires short-termworking memory to receive test information and long-term memory to recognize and name the odor, so a nor-mal olfactory performance requires the integrity of bothprimary olfactory cortex and higher order cognitive net-work such as the limbic network and is modulated byvaries neural transmitters [70].Focal voxel-based morphology analysis of the olfactorysulcus showed smaller depth in the PD patients but thisdid not correlate with olfactory identification perform-ance [68], while the grey matter volume in the piriformcortex was positively correlated with the olfactory per-formance in early PD subjects [71].In both PD and healthy controls, olfactory stimulationactivated vast brain regions in functional magnetic res-onance imaging, including amygdaloid complex, hippo-campal formation, lateral orbitofrontal cortex, striatum,thalamus and midbrain; compared to control subjects,the activation in amygdala and hippocampal formationwas reduced in PD patients [72]. In a study using olfac-tory event-related potentials to identify hyposmia, fur-ther decrease of activation was found in the inferiorfrontal gyrus, insula and cingulate cortex as well as inamygdala and hippocampus in PD without identifiableolfactory event-related potentials [73]. Other cortical re-gions with decreased activation in hyposmic PD includedmedial frontal gyrus, middle temporal gyrus and occipi-tal cortex [74]. In resting state, the regional homogeneityand functional connectivity within primary olfactory cor-tices and secondary olfactory structures were reduced inhyposmic PD; along with significantly decreased con-nectivity within limbic/paralimbic networks betweengyrus rectus and orbital frontal cortex, parahippocampalgyrus, middle occipital gyrus, insula, temporal pole,posterior cingulate and amygdala [75]. A longitudinal18F-fluorodeoxyglucose PET study showed reducedmetabolism in bilateral medial prefrontal cortex andparieto-occipito-temporal cortex in hyposmic PD at base-line and a marked metabolic reduction in the posterior re-gions such as posterior cingulate, precuneus, medialoccipital and parieto-occipito-temporal cortex at 3-yearfollow-up; this pattern of reduced metabolism has someextent of similarity with the PD-related cognitive patternreported by the Eidelberg group [76, 77]. The PD groupwith hyposmia had significant deteriorations in Mini-Mental State Examination score compared to normosmicPD and one standard deviation change in the olfactoryscore at baseline resulted in 18.7-fold increase in the riskof developing PD with dementia in 3 years [76].The connection between olfactory impairment andcognitive decline was further revealed by PET studies:positive correlations between UPSIT scores and acetyl-cholinesterase (AChE) activities were found in the hippo-campal formation, amygdala and neocortex (R = 0.56,P < 0.0001; R = 0.50, P < 0.0001; R = 0.46, P = 0.0003;respectively); while limbic AChE activity also corre-lated positively with executive cognitive ability (r = 0.36,P = 0.006) and verbal memory (r = 0.29, P = 0.03) [70]. Inthe same study, higher UPSIT scores were associated withbetter scores on cognitive measures, revealing the sameunderlying cholinergic mechanism behind olfactory defi-cits and cognitive decline. To date, the linkage betweenhyposmia and cognitive disorder were reported fromsymptomatic level, structure level, resting-state and event-related functional level, metabolic level and neurotrans-mitter level [45, 70, 75, 76].Olfactory function has been reported to correlate withthe integrity of other neurotransmitter systems in PD,such as binding potential of vesicular monoamine trans-porter type 2 in the striatum (R = 0.30, P < 0.05) andbinding potential of DAT in the hippocampus, amygdalaand striatum (RS = 0.54, P = 0.003; RS = 0.43, P = 0.02;RS = 0.48, P = 0.008; respectively) [70, 78]. There islack of significant correlation between binding potential ofserotonin transporter in the raphe nucleus, amygdala,hippocampus, striatum or neocortex [79], which is contra-dictory to the results from animals [80, 81]. A summary ofimportant imaging evidence regarding parasympatheticnervous system and olfactory system was provided inTable 1. Association with decrease of odor identificationcapability and striatum DAT binding were also reported ingeneral aged populations, patients with “idiopathic” olfac-tory loss and high-risk populations such as leucine-richrepeat kinase 2 (LRRK2) G2019S carriers [22, 44, 49,82, 83]. However, it is difficult to know whether thisreflects a true relationship between the dopaminergicloss and olfactory dysfunction or whether both find-ings might simply reflect underlying prodromal PD.The internal homogeneity and heterogeneity ofprodromal mechanismsIn fact, the linkage between different prodromal symp-toms and imaging signs of prodromal PD are universal.Hyposmia has been associated with constipation, depres-sion, anxiety and mild motor symptoms [45], a combin-ation of symptoms is more predictive of decreased DATbinding [22]. Other studies showed linkage betweenhyposmia, symptoms of autonomic failure and imagingevidence of sympathetic system denervation, such as lowercardiac septal: hepatic ratios of 6-18F-fluorodopamine-de-rived radioactivity and lower cardiac 123I-metaiodobenzyl-guanidine uptake [84–86]. In both manifest PD with RBDand idiopathic RBD patients, RBD has been linked withLiu et al. Translational Neurodegeneration  (2017) 6:4 Page 5 of 9hyposmia, constipation, orthostatic symptoms, hallucina-tions, depression and worse parkinsonian sign [87, 88]. Inpopulation-based studies, substantia nigra hyperechogeni-city has been associated with constipation, hyposmia, de-pression and mild parkinsonian signs [89].The cause of this clustering of motor and non-motorsymptoms is unknown, although different classificationsof empirical subtypes based on the clusters are proposed[90], the phenomena may simply follow the severity ofpathological development of PD. Hyposmia, RBD andconstipation constantly appear in different clusters,while the corresponding pathological structures are ei-ther the potential portals for α-syn aggregation (DMVand olfactory system) or are close to them (locus coeru-leus/subcoeruleus complex and pedunculopotine nu-cleus), so it is natural that the symptoms should clustertogether if α-syn propagates though the relevant struc-tures. In support of this view, some evidence showedpossible higher α-syn burden in subjects with hyposmia,RBD and reduced 123I-metaiodobenzylguanidine uptake[91–93], in agreement with the Braak stage and the pro-gression of PD. From this perspective, the homogeneityin the development of parkinsonian pathology is empha-sized, and the recently described research criteria forprodromal PD assign each symptom and sign in thoseclusters into a combined score to predict future PDmanifestation [5].On the other hand, such a scheme may neglect im-portant heterogeneity of mechanisms in the develop-ment of PD. Braak and colleagues have proposed a dual-hit hypothesis in which a neurotropic pathogen mightenter the brain through either the gastrointestinal or thenasal route [94], either of which can result in diseaseprogression, but potentially with different manifestations[95, 96]. Empirical nonmotor subtypes are recently pro-posed, which categorize patients into brainstem pheno-type (brainstem route, characterized with late onsethyposmia, RBD and dysautonomia), limbic phenotype(olfactory route, characterized by anosmia, depression,fatigue and central pain) and cognitive phenotype(diffused, characterized by cognitive decline) [97, 98].So far, no pathological evidence is available to supportsuch subtyping and the internal axonal linkage betweenthe olfactory bulb, olfactory cortex and basal forebrain,hypothalamus, and brainstem may introduce ambiguity inthe separation of the two hypothetical routes [99, 100].However, functional and structural network analysis basedon neuroimaging may help to investigate the real propaga-tion patterns of α-syn pathology in the brain.Another illustration of heterogeneity in PD is based ongenetic subtypes, as there is evidence of pathophysio-logical differences related to certain gene mutations,such as increased inflammation in LRRK2 mutation car-riers [101, 102]. The lack or lesser extent of α-syn depos-ition in some genetic forms of PD further emphasizesthese differences [103]. Compared to RBD patients,LRRK2 carriers have significantly lower prevalence of ol-factory loss, cognitive decline or sleep disturbance in theprodromal stage [104–108]. Neuroimaging studies areneeded to consider the functional and structuralTable 1 Summary of pathological and imaging evidence of parasympathetic nervous system and olfactory system involvement in PDStructure α-syn pathology Structural imaging Functional imaging Molecular imagingVagus nerve Positive NA NA NAGastrointestinal tract Controversy NA NA Decreased 11C-donepezil standarduptake values in the small intestineand pancreas following a rostral-caudal gradient [43]Olfactory bulb Positive Bilateral reduction of olfactorybulb volume [64, 65, 68]NA NAOlfactory tract Positive Bilateral increase of meandiffusivity [66, 67]NA NAOlfactory cortex Positive Decrease of olfactory sulcusdepth; decrease of piriformcortex volume [68, 71]Reduced activation in amygdalaand hippocampal formation afterolfactory stimulation [72–74];decreased regional homogeneityand functional connectivity withinolfactory cortex and decreasedconnectivity within limbic/paralimbic networks [75]Reduced glucose metabolism inbilateral medial prefrontal cortexand parieto-occipito-temporalcortex [76]; positive correlationsbetween UPSIT scores and acetylcholinesterase activities in hippocampal formation, amygdala andneocortex [70]; positive correlationsbetween UPSIT scores and vesicularmonoamine transporter type 2binding potential in striatum [70];positive correlations between UPSITscores and dopamine transporterbinding potential in hippocampus,amygdala and striatum [78]Liu et al. Translational Neurodegeneration  (2017) 6:4 Page 6 of 9network changes in the genetic subtypes and to evaluatethe differences between the sporadic subtypes and gen-etic subtypes in both non-manifest and manifest stages.Even though not emphasized in this review, the sym-pathetic nervous system may deserve more attention inattempting to understand mechanisms of prodromal PD,as there is evidences for pre-motor involvement of per-ipheral noradrenergic depletion [109], while the norad-renergic nucleus locus coeruleus may be affected priorto the substantia nigra in the prodromal stage. Relatedbiomarker such as 123I-metaiodobenzylguanidine uptakeand 3-methoxy-4-hydroxyphenylglycol can be potentialearly indicators for central neurodegeneration [110].ConclusionsThe underlying mechanism of prodromal PD includesboth homogeneous and heterogeneous aspects. A-synmay proliferate in a prion-like manner and selectivelycause neurodegeneration, which possibly represents asthe Braak stage in pathology and lead to clusters of pro-dromal symptoms and signs in clinic; while the gastro-intestinal tract/vagus nerve and olfactory system can betwo separate routes and models of pathological progres-sion. Further efforts are needed using neuroimaging as atool to investigate the network changes.AbbreviationsAChE: Acetylcholinesterase; CBD: Corticobasal degeneration; DAT: Dopaminetransporter; DMV: Dorsal motor nucleus of the glossopharyngeal and vagusnerves; DTI: Diffusion tensor imaging; HR: Hazard ratio; LR: Likelihood ratio;LRRK2: Leucine-rich repeat kinase 2; MRI: Magnetic resonance imaging;MSA: Multiple system atrophy; OR: Odds ratio; PD: Parkinson’s disease;PET: Positron emission tomography; Pser129: Alpha-synuclein phosphorylatedon serine 129; PSP: Progressive supranuclear palsy; RBD: REM sleep behaviordisorder; RR: Relative risk; TDP43: TAR DNA-binding protein 43; UPSIT: Universityof Pennsylvania Smell Identification Test; α-syn: Alpha-synucleinAcknowledgementsNot applicable.FundingNot applicable.Availability of data and materialsData sharing not applicable to this article as no datasets were generated oranalyzed during the current study.Authors’ contributionsSYL made substantial contributions to design and draft the manuscript; PCwas involved in revising it; AJS designed, revised the manuscript; All theauthors read and gave final approval of the manuscript to be published.Competing interestsThe authors declare that they have no competing interests.Consent for publicationNot applicable.Ethics approval and consent to participateNot applicable.Author details1Department of Neurobiology, Neurology and Geriatrics, Xuanwu HospitalCapital Medical University, Beijing 100051, China. 2Beijing Key Laboratory onParkinson’s Disease, Parkinson Disease Center of Beijing Institute for BrainDisorders, Beijing 100051, China. 3Pacific Parkinson’s Research Centre, Divisionof Neurology and Djavad Mowafaghian Centre for Brain Health, University ofBritish Columbia and Vancouver Coastal Health, Vancouver V6T 1Z3, BC,Canada.Received: 15 January 2017 Accepted: 7 February 2017References1. 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